Use of benzoylalkyl-1,2,3,6-tetrahydropyridines

ABSTRACT

The invention relates to the use of compounds of formula  
                 
 
     for the preparation of medicines designed for the treatment of neuronal and cerebral disorders.  
     The invention also relates to the compounds of formula:  
                 
 
     a process for their preparation and the pharmaceutical compositions containing them.

[0001] The present invention relates to the use of certainbenzoyl-1,2,3,6-tetrahydropyridines as neurotrophic and neuroprotectiveagents as well as of novel derivatives, a process for their preparationand pharmaceutical compositions containing them.

[0002] EP-0 458 696 describes the use of a1-(2-naphthylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinefor the preparation of medicines designed for the treatment of cerebraland neuronal disorders.

[0003] WO 91/08200 describes derivatives of tetrahydropyridine withprotective activity towards damage caused by hypoxic/ischemic states.

[0004] WO 93/11107 describes certain ketones used as intermediates inthe preparation of the corresponding alcohols.

[0005] It has now been found that certainbenzoyl-1,2,3,6-tetrahydropyridines exert a neutrotrophic action on thenervous system similar to that of the nerve growth factor (NGF) and mayrestore the function of the damaged cells or cells exhibiting anomaliesin their physiological functions.

[0006] Hence, according to one of its features, the present inventionrelates to the use of compounds of formula (I)

[0007] in which

[0008] R₁ is halogen, a CF₃, (C₁—C₄) alkyl or (C₁—C₄) alkoxy group;

[0009] n is 0 or 1

[0010] R₂ is hydrogen or a (C₁—C₄) alkyl group;

[0011] R₃ is hydrogen, (C₁—C₆) alkyl, (C₁—C₆) alkoxy; halogen; a CF₃group, hydroxy, a group selected from (C₃—C₇) cycloalkyl, phenyl,phenoxy, phenylmethyl or phenylethyl, said group being optionally mono-or polysubstituted on the phenyl group by halogen, CF₃, (C₁—C₄) alkyl or(C₁—C₄) alkoxy;

[0012] R₄ and R₅ is each independently hydrogen, (C₁—C₆) alkyl, (C₁—C₆)alkoxy, halogen, a CF₃ group or hydroxy;

[0013] as well as to their salts and solvates and their quaternaryammonium salts, for the preparation of medicines designed for thetreatment and/or the prophylaxis of the diseases which involve neuronaldegeneration.

[0014] In the present description the term “(C₁—C₄) alkyl” designatesthe groups methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyland t-butyl.

[0015] The term “(C₁—C₆) alkyl” designates a hydrocarbon radicalcontaining from 1 to 6 carbon atoms such as, for example, methyl, ethyl,n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,neopentyl, t-pentyl, n-hexyl, i-hexyl.

[0016] When R₃ is a phenyl group, the nomenclature given to the biphenylradical is that in conformity with the IUPAC rules, namely the numberingof the positions of the two rings is the following:

[0017] and the radicals having this structure are named:

[0018] Among the compounds of formula (I), a preferred group isconstituted by the compounds of formula (I) where n is zero.

[0019] Another preferred group is constituted by the compounds offormula (I) where R₂ is hydrogen.

[0020] Another preferred group is constituted by the compounds offormula (I) where one of R₃, R₄ and R₅ is hydrogen.

[0021] Particularly advantageous compounds according to the presentinvention are the compounds of formula (I) where the group R₁ is a CF₃group in position 3 of the phenyl group.

[0022] Among the compounds of formula (I) those of formula (I′)

[0023] in which

[0024] R′₁ is halogen, a CF₃, (C₁—C₄) alkyl or (C₁—C₄) alkoxy group;

[0025] R′₂ is (C₁—C₆) alkyl, (C₁—C₆) alkoxy; halogen, a CF₃ group,hydroxy, a group selected from (C₃—C₇) cycloalkyl, phenyl, phenoxy,phenylmethyl or phenylethyl, said group being optionally mono- orpolysubstituted on the phenyl group by halogen, CF₃, (C₁—C₄) alkyl or(C₁—C₄) alkoxy;

[0026] R′₃ is hydrogen, (C₁—C₆) alkyl, (C₁—C₆) alkoxy, halogen, a CF₃ orhydroxy group;

[0027] as well as their salts and solvates and their quaternary ammoniumsalts, are novel compounds and constitute a further feature of thepresent invention.

[0028] The preferred quaternary ammonium salts are those of formula (I″)

[0029] where X— is a pharmaceutically acceptable anion, preferablyCl—,Br—,I—, CH₃SO₃—, C₆H₅SO₃— and Alk being (C₁—C₄) alkyl, preferablymethyl.

[0030] Among the compounds of formula (I′), particularly advantageouscompounds are the following:

[0031]1-{2-(3′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0032]1-{2-(2′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0033]1-{2-(4′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0034]1-{2-(4-isobutylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0035]1-{2-(4-benzylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0036]1-{2-(4-cyclohexylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0037]1-{2-(4′-fluorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0038]1-{2-(4-n-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0039]1-{2-(biphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0040]1-{2-(4-t-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0041]1-{2-(3,4-diethylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0042]1-{2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0043]1-{2-(3′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0044]1-{2-(4′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;

[0045] as well as their salts and solvates.

[0046] The compounds of formula (I) are prepared as described in WO91/08200 and WO 93/11107.

[0047] According to another of its features, the present inventionrelates to a process for the preparation of the compounds of formula(I′), their salts or solvates and their quaternary ammonium salts,characterized in that

[0048] (a) an aryl-1,2,3,6-tetrahydropyridine of formula (II)

[0049]  in which R′₁ is as defined above, is reacted with a compound offormula (III)

[0050] in which R′₂ and R′₃ are as previously defined and L is a leavinggroup such as, for example, a chlorine, bromine or iodine atom or amethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy,trifluoromethylsulfonyloxy group, bromine being preferred; and

[0051] (b) the compound of formula (I′) thus obtained is isolated andoptionally converted into one of its salts or solvates or one of itsquaternary ammonium salts.

[0052] The reaction is carried out in an organic solvent at atemperature included between room temperature and the reflux temperatureof the solvent used.

[0053] An aliphatic alcohol having from 1 to 6 carbon atoms such asmethanol, ethanol, isopropanol, n-butanol, n-pentanol is used aspreferred organic solvent, but other solvents such as hexane,dimethylformamide, dimethylsulfoxide, sulfolane, acetonitrile, pyridineand the like may also be used.

[0054] The reaction is advantageously carried out in the presence of abasic agent such as an alkali hydroxide or carbonate or triethylamine,particularly in the case where L is a halogen atom.

[0055] The reaction temperature may vary between room temperature (about20° C.) and that of reflux and the reaction times vary accordingly. Ingeneral, the reaction is terminated after 0.5 to 12 hours of heating atreflux and the final product thus obtained can be isolated according toconventional procedures in the form of the free base or one of its saltsor solvates and the free base is optionally converted into one of itssalts by simple salification in an organic solvent such as an alcohol,preferably ethanol or isopropanol, an ether like 1,2-dimethoxyethane,ethyl acetate, acetone or a hydrocarbon like hexane.

[0056] The compound of formula (I′) obtained and isolated according tothe usual procedures is optionally converted into one of its quaternaryammonium salts by reaction with an alkyl halide of formula (IV)

Alk-Hal   (IV)

[0057] where Alk is (C₁—C₄) alkyl and Hal is chlorine, bromine oriodine.

[0058] The quaternary ammonium salt of formula (I″a) thus obtained

[0059] can be converted into another salt for example by an (X—) chargedanion exchange resin, where X— is a pharmaceutically acceptable anionother than Hal, and preferably the CH₃SO₃—, C₆H₅SO₃— or p-CH₃—C₆H₅SO₃—(paratoluenesulfonyloxy) anion.

[0060] When the salts of the compounds of formula (I) and (I′) areprepared to be administered as medicines, the acids used must bepharmaceutically acceptable; if the salts of the compounds of formula(I) and (I′) are prepared for another purpose, for example to improvethe purity or facilitate analytical tests or to separate the enantiomersin the presence of a chiral carbon atom, then any suitable acid or basemay be used.

[0061] The salts with pharmaceutically acceptable acids are, forexample, those with mineral acids such as hydrochloride, hydrobromide,borate, phosphate, sulfate, hydrogen sulfate, hydrogen phosphate ordihydrogen phosphate and those with organic acids such as citrate,benzoate, ascorbate, methylsulfate, naphthalene-2-sulfonate, picrate,fumarate, maleate, malonate, oxalate, succinate, acetate, tartrate,mesylate, tosylate, isethionate, a-ketoglutarate, a-glycerophosphate orglucose-1-phosphate.

[0062] The starting amines of formula (II) are known compounds or theycan be prepared according to processes similar to those used to preparethe known compounds.

[0063] The compounds of formula (III) can be prepared by reaction of theappropriate benzene of formula (V)

[0064] in which R′₂ and R′₃ are as previously defined, with an acylhalide of formula L-CH₂—CO-Hal in which L and Hal are as previouslydefined, in the presence of a Lewis acid according to the well-knownFriedel-Crafts reaction.

[0065] Alternatively, the starting materials (III) where R′₂ is anoptionally substituted phenyl group may also be prepared by carrying outthe Suzuki reaction by working in an aqueous medium, namely bycondensation between phenyl derivatives substituted by a leaving groupand benzeneboronic acids in the presence of a catalyst, strong base(s)and phase transfer agent according to the conditions described by D.Badone et al., 212th ACS National Meeting, American Chemical Society,Orlando Fla., Aug. 25-29 1996, Abstract 351).

[0066] The activity of the compounds of formula (I), in particular thatof the compounds (I′), on the nervous system was demonstrated in invitro and in vivo studies according to the methods described in EP-0 458696 and neuronal survival was evaluated with the aid of an in vitrosurvival test performed by using isolated neurons from dissections ofthe septal region of rat embryos.

[0067] More particularly, a sample of the septal region of 17-18 daysold rats was taken under a dissection microscope under sterileconditions, then it was dissociated in trypsin-EDTA medium. The cellsuspension was placed in a culture flask in DME/Ham's P12 medium (v:v)Dulbecco Modified Eagle medium/Ham's F12 Nutrient mixture—R. G. Ham,Proc. Nat. Sci.,1965, 53 : 288) containing 5% calf serum and 5% horseserum and maintained at 37° C. for 90 minutes. This treatment permitsthe elimination of non-neuronal cells.

[0068] The neuroblasts are then inoculated into the wells of a titrationplate at 17×10⁴ cells/cm² in a non-serum culture medium constituted byDME/Ham's F12 containing selenium (30 nM) and transferrin (1.25 mM).Each well was subject to prior treatment with poly-L-lysine. Theinoculated plates are placed in an incubator (37° C.; 5% CO2).

[0069] The test compounds are dissolved in DMSO and diluted as requiredby the culture medium.

[0070] The neuroblasts are maintained on plates containing the testcompound or the corresponding solvent for 4 days without changing themedium.

[0071] After 4 days the medium is replaced by culture medium in which atetrazolium salt is dissolved (0.15 mg/ml). The cells are then placed inthe incubator at 37° C. for 4 hours. The mitochondrial succinatedehydrogenases of the living cells reduce the tetrazolium salt toformazan blue, the optical density of which is measured at 540 nm afterdissolution in DMSO and which is linearly correlated with the number ofliving cells (Manthorpe et al., Dev. Brain Res., 1988, 25: 191-198).

[0072] The difference between the groups containing the test compoundsand the controls was evaluated by statistical analysis using thetwo-tailed Dunnett t-test.

[0073] In this latter test the compounds of formula (I), in particularthose of formula (I′), proved to be as active or more active than thecompounds described in EP-0 458 696, the efficacy of certain compoundsof formula (I′) on the neuronal survival being twice that of compound Adescribed in EP-0 458 696.

[0074] As a result of this potent neuroprotective activity and their lowtoxicity compatible with use as medicines, the compounds of formula (I),in particular those of formula (I′), as well as their pharmaceuticallyacceptable addition salts, their solvates and their quaternary ammoniumsalts, in particular those of formula (I″), may be used for thepreparation of pharmaceutical compositions indicated in the treatmentand/or prophylaxis of all diseases which involve neuronal degeneration,a use which constitutes a further feature of the present invention. Moreparticularly, the invention relates to the use of the compounds offormula (I), in particular (I′) and (I″), alone or on co-administrationor combination with other active ingredients acting on the CNS, forexample, acetylcholinesterase inhibitors, selective M1 cholinomimetics,NMDA antagonists, nootropics such as piracetam in the followingindications:memory disorders, vascular dementia, post-encephaliticdisorders, post-apoplectic disorders, post-traumatic syndromes due to acranial traumatism, Alzeheimer's disease, senile dementia, subcorticaldementia, such as Huntington chorea and Parkinson's disease, dementiacaused by AIDS, neuropathies resulting from morbidity or damage tosympathetic or sensory nerves,cerebral diseases such as cerebral oedemaand spinocerebellar degenerations, degeneration of motoneurons like forexample amyotrophic lateral sclerosis.

[0075] The administration of the compounds accordiing to the inventionmay be suitably performed by the oral, parenteral, sublingual ortransdermal route. The quantity of active ingredient to be administeredin the treatment of cerebral and neuronal disorders according to themethod of the present invention depends on the nature and gravity of thediseases to be treated as well as on the weight of the patients. Ingeneral, the total dose in man varies between 1 and 1400 mg per day,advantageously between 2 and 900 mg per day, for example 3 to 500 mg,more suitably from 10 to 300 mg per day in pharmaceutical compositions.The compositions of the present invention are preferably administered inthe form of dosage units. These unit doses will usually comprise from0.5 to 700 mg, advantageously from 2 to 300 mg, preferably from 5 to 150mg, for example between 5 and 50 mg, namely 1, 2, 5, 10, 15, 20, 25, 30,40 or 50 mg of product. These unit doses will usually be administeredonce or several times a day, for example 2, 3, 4 or 5 times per day,preferably one to three times a day.

[0076] According to another of its features, the object of the presentinvention is a pharmaceutical composition containing as activeingredients a compound of formula (I) above and a compound indicated inthe symptomatic treatment of senile dementia of the Alzheimer type (DAT)or their pharmaceutically acceptable salts.

[0077] The expression “compound indicated in the symptomatic treatmentof senile dementia of the Alzheimer type (DAT)” indicates a productwhich is capable of improving the symptomatology of the patientssuffering from DAT without having any effect on the causes of thedisease.

[0078] Such compounds are for example acetylcholinesterase inhibitors,M₁ muscarinic agonists, nicotinic agonists, NMDA receptor antagonists,nootropic agents.

[0079] Preferred acetylcholinesterase inhibitors are tacrine anddonepezil.

[0080] Other acetylcholinesterase inhibitors which may be used are forexample rivastigmine (SDZ-ENA-713), galanthamine, metrifonate,eptastigmine, velnacrine, physostigmine (Drugs, 1997, 53 (5): 752-768;The Merck Index 12 ed.).

[0081] Other acetylcholinesterase inhibitors are also5,7-dihydro-3-{2-{1-(phenylmethyl)-4-piperidinyl}ethyl}-6H-pyrrolo{3,2-f}-1,2-benzisoxazol-6-one, also known as icopezil (J. Med. Chem.,1995, 38: 2802-2808), MDL-73,745 or zifrosilone (Eur. J. Pharmacol.,1995, 276: 93-99), TAK-147 (J. Med. Chem., 1994, 37: 2292-2299).

[0082] Other acetylcholinesterase inhibitors are for example those whichare described in the patent applications JP 09-095483, WO 97/13754, WO97/21681, WO 97/19929, ZA 96-04565, U.S. Pat. No. 5,455,245, WO95-21822, EP 637 586, U.S. Pat. No. 5,401,749, EP 742 207, U.S. Pat. No.5,547,960, WO 96/20176, WO 96/02524, EP 677 516, JP 07-188177, JP07-133274, EP 649 846, EP 648 771, JP 07-048370, U.S. Pat. No.5,391,553, WO 94/29272, EP 627 400.

[0083] According to another of its features, the present inventionrelates to a pharmaceutical composition containing as active ingredienta compound of formula (I) and an M₁ receptor agonist, or theirpharmaceutically acceptable salts.

[0084] M₁ receptor agonists are, for example, milameline, besipiridine,talsaclidine, xanomeline, YM-796 and YM-954 (Eur. J. Pharmacol., 1990,187: 479-486),3-{N-(2-diethylamino-2-methylpropyl)-6-phenyl-5-propyl}-pyridazinamine,also known as SR-46559 (Biorg. Med. Chem. Let., 1992, 2: 833-838),AF-102, CI-979, L-689,660, LU 25-109, S-99 77-2, SB 202,026,thiopilocarpine, WAL 2014 (Pharmacol. Toxicol., 1996, 78: 59-68).

[0085] According to another feature, the invention relates to apharmaceutical composition containing as active ingredient a compound offormula (I) and a nicotinic agonist or their pharmaceutically acceptablesalts.

[0086] Advantageous nicotinic agonists are for example MKC-231 (Biorg.Med. Chem. Let., 1995, 5 (14): 1495-1500), T-588 (Japan J. Pharmacol.,1993, 62: 81-86), ABT-418 (Br. J. Pharmacol., 1997, 120: 429-438).

[0087] According to another feature, the invention relates to apharmaceutical composition containing as active ingredient a compound offormula (I) and an N-methyl-D-aspartate (NMDA) receptor antagonist ortheir pharmaceutically acceptable salts.

[0088] A particularly advantageous NMDA receptor antagonist is, forexample, memantine (Arzneim. Forsch., 1991, 41, 773-780).

[0089] According to another feature, the invention relates to apharmaceutical composition containing as active ingredient a compound offormula (I) and a nootropic agent or their pharmaceutically acceptablesalts.

[0090] Nootropic agents which may be used according to the inventionare, for example, netiracetam and nebracetam (Merck Index, 12th ed.).

[0091] The doses of the two combined active ingredients are usuallyselected from the doses of each medicine which would be administered inan uncombined treatment.

[0092] In accordance with another feature, the present invention alsorelates to a method for the treatment of senile dementia of theAlzheimer type which consists of the administration to a patientsuffering from this disease of an efficacious dose of a compound offormula (I) or of one of its pharmaceutically acceptable salts and of anefficacious dose of a compound indicated in the symptomatic treatment ofDAT or of one of its pharmaceutically acceptable salts, saidadministrations being simultaneous, sequential or alternating atintervals and the efficacious doses of the active ingredients beingcontained in separate unit forms of administration or, when the activeingredients are administered simultaneously, the two active ingredientsbeing advantageously contained in a single pharmaceutical form.

[0093] Thus, the present invention relates, in accordance with anotherof its features, to pharmaceutical compositions containing as activeingredient a compound of formula (I′) or one of its pharmaceuticallyacceptable salts or solvates or one of its quaternary ammonium salts, inparticular of formula (I″).

[0094] In the pharmaceutical compositions of the present invention fororal, sublingual, subcutaneous, intramuscular, intravenous, transdermalor rectal administration, the active ingredient may be administered in aunit form of administration, either as such for example, in lyophilizedform or in a mixture with standard pharmaceutical vehicles, to animalsand to human beings for the treatment of the above-mentioned diseases.The appropriate unit forms of administration include the oral forms suchas optionally divisible tablets, capsules, powders, granules and oralsolutions or suspensions, the forms for sublingual and buccaladministration, the forms for subcutaneous, intramuscular or intravenousadministration, the forms for topical administration and the forms forrectal administration.

[0095] When a solid composition is prepared in the form of tablets, theprincipal active ingredient is mixed with a pharmaceutical vehicle suchas gelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets may be coated with sucrose or other suitable materialsor they may also be treated so that they have a prolonged or delayedactivity and so that they continuously release a predefined quantity ofactive ingredient.

[0096] A preparation of capsules is obtained by mixing the activeingredient with a diluent and by pouring the mixture obtained into softor hard capsules.

[0097] A preparation in the form of a syrup or elixir may contain theactive ingredient together with a sweetening agent, preferablycalorie-free, methylparaben and propylparaben as antiseptics, as well asa flavouring agent and a suitable colouring matter.

[0098] The powders and granules dispersible in water may contain theactive ingredient in a mixture with dispersion agents or wetting agents,or suspension agents like polyvinylpyrrolidone, and also with sweeteningagents or flavour correctors.

[0099] For rectal administration, recourse is had to suppositories whichare prepared with binders melting at the rectal temperature, forexample, for example cocoa butter or polyethyleneglycols.

[0100] For parenteral administration, aqueous suspensions, salinesolutions or sterile and injectable solutions which containpharmacologically compatible dispersion and/or wetting agents, forexample propyleneglycol or butyleneglycol, are used.

[0101] The active ingredient may also be formulated in the form ofmicrocapsules, optionally with one or more vehicles or additives.

[0102] In the pharmaceutical compositions according to the presentinvention, the active ingredient may also be in the form of an inclusioncomplex in cyclodextrins, their ethers or their esters.

[0103] The examples which follow provide a better illustration of theinvention.

EXAMPLE 1

[0104]1-{2-(3′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0105] 1a/1-bromo-2-(3′-chlorobiphenyl-4-yl) ethanone

[0106] A mixture of 5 g (0.026 mole) of 3-chlorobiphenyl, 50 ml ofmethylene chloride, 6.95 g (0.034 mole) of bromoacetyl bromide is cooledto 0-5° C. and 4 g (0.030 mole) of aluminium trichloride are added. Themixture is stirred for 1 hour at 5° C., then for 4 hours at roomtemperature. It is poured onto an ice/water mixture, extracted withmethylene chloride, the organic phase is washed with a 1N solution ofHCl, dried over sodium sulfate and evaporated under reduced pressure.4.5 g of the title product is obtained. M.p. 63-65° C.

[0107]1b/1-{2-(3′-chlorobiphenyl-4-yI)-2-oxoethyl}-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0108] A mixture of 0.4 g (0.013 mole) of the product from the previousstep, 2.95 g (0.013 mole) of4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine, 80 ml ofethanol and

[0109] 2.32 g (0.0167 mole) of powdered anhydrous potassium carbonate isheated at reflux for 1 hour. The salts are removed by filtration and thesolution is acidified by addition of a hydrochloric acid-saturatedethanol solution. It is concentrated to about 40 ml under reducedpressure and left to stand overnight at 5° C. The precipitate is filteroff, washed with water and then with isopropanol. 4.9 g of the titlecompound are obtained. M.p. 217-220° C.

EXAMPLE 2

[0110]1-{2-(2′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0111] On working as described in Example 1 but by using2-chloro-biphenyl instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 200-202° C. (crystallized from isopropanol).

EXAMPLE 3

[0112]1-{2-(4′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0113] On working as described in Example 1 but by using4-chloro-biphenyl instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 210-215° C.

EXAMPLE 4

[0114]1-{2-(4-isobutylphenyl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0115] On working as described in Example 1 but by using4-isobutyl-benzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 224-228° C. (crystallized from isopropanol).

EXAMPLE 5

[0116]1-{2-(4-phenoxyphenyl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0117] On working as described in Example 1 but by using diphenyl-etherinstead of 3-chlorobiphenyl, the title compound is obtained. M.p.205-210° C.

EXAMPLE 6

[0118]1-{2-(4-cyclohexylphenyl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0119] On working as described in Example 1 but by usingcyclo-hexylbenzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 209-213° C. (crystallized from isopropanol).

EXAMPLE 7

[0120]1-{2-(4′-fluorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0121] On working as described in Example 1 but by using4-fluoro-biphenyl instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 123-125° C. (crystallized from isopropanol).

EXAMPLE 8

[0122]1-{2-(biphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0123] On working as described in Example 1 but by using biphenylinstead of 3-chlorobiphenyl, the title compound is obtained. M.p.145-147° C. (base); m.p. 240-243° C. (hydrochloride).

EXAMPLE 9

[0124]1-{2-(4-n-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0125] On working as described in Example 1 but by using4-n-butyl-benzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 218-221° C.

EXAMPLE 10

[0126]1-{2-(4-t-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0127] On working as described in Example 1 but by using4-t-butyl-benzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 97-9° C. (base).

EXAMPLE 11

[0128]1-{2-(3,4-diethylphenyl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0129] On working as described in Example 1 but by using3,4-diethylbenzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 232-234° C.

EXAMPLE 12

[0130]1-{2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0131] 12a/2-(4-bromophenyl)-2,2-dimethoxyethane

[0132] A mixture of 2 g (0.01 mole) of 4-bromoacetophenone, 5.6 ml oftrimethyl orthoformate, 5.6 ml of methanol and 0.67 g of Amberlite® IR120 is heated at reflux for 3 hours. After cooling, the mixture isfiltered through Celite® and the filtered solution is evaporated. 2.4 gof the title compound are obtained in the form of an oil.

[0133] 12b/2,2-dimethoxy-2-(2′-trifluoromethylbiphenyl-4-yl) ethane

[0134] A mixture of 4.9 g (14 mmole) of the product from the previousstep, 2.45 g (16 mmole) of 2-trifluoromethylbenzene-boronic acid, 63 mg(0.28 mmole) of palladium acetate, 4.84 g (35 mmole) of potassiumcarbonate and 4.5 g (14 mmole) of tetrabutylammonium bromide in 19 ml ofwater is stirred at 70° C. for 1 hour. It is allowed to cool andextracted with ethyl acetate. The organic phase is dried over sodiumsulfate, filtered and the solvent is evaporated under reduced pressure.The title compound is obtained in the form of an oil.

[0135] 12c/4-(2-trifluorophenyl) acetophenone

[0136] A solution of 4 ml of trifluoroacetic acid and 4 ml of water isadded at 0° C. to a solution of 4.6 g (0.0105 mole) of the product fromthe previous step in 4 ml of methylene chloride. The mixture is stirredat room temperature for 2 hours, poured into water and extracted withmethylene chloride. The organic phase is dried, filtered and the solventis evaporated under reduced pressure. The crude product is purified bychromatograpphy on a silica gel column by elution with acyclohexane/ethyl acetate mixture=9/1. 1.97 g of the title compound areobtained.

[0137] 12d/ a-bromo-4-(2-trifluoromethylphenyl) acetophenone

[0138] To a solution of 1.97 g (7.5 mmole) of the product from theprevious step in 5.4 ml of methanol, 0.38 ml (7.5 mmole) of bromine isadded dropwise at 0° C. The mixture is stirred at room temperature for 3hours, the solvent is evaporated, the residue is taken up in water andthe solution is extracted with ethyl acetate. The organic phase is driedover sodium sulfate, filtered and the solvent is evaporated underreduced pressure. The title compound is obtained.

[0139]12e/1-{2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0140] A mixture of 0.74 g (0.0028 mole) of4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine, 14 ml ofethanol and 1.27 g (0.0092 mole) of powdered anhydrous potassiumcarbonate is heated at reflux for 1 hour. A solution of 1.2 g (0.0035mole) of the oil from the previous step in 3 ml of ethanol is added andrefluxed for 30 minutes. The salts are removed by filtration and thesolution is acidified by addition of a 1N aqueous solution ofhydrochloric acid. The solvent is evaporated under reduced pressure, theresidue is extracted with chloroform, the organic phase is dried oversodium sulfate, filtered and the solvent is evaporated under reducedpressure. The free base is obtained with the aid of a concentratedsolution of ammonia and extracted with ethyl acetate and the product ispurified by chromatography on a silica gel column by elution with acyclohexane/ethyl acetate mixture=8/2. The title compound is obtained.The hydrochloride is prepared with the aid of an isopropanol solutionsaturated with hydrochloric acid. M.p. 195-197° C.

EXAMPLE 13

[0141]1-{2-(3′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0142] On working as described in Example 12 but by using3-trifluoromethylbenzeneboronic acid instead of2-trifluoromethylbenzeneboronic acid in step 12b/, the title compound isobtained. M.p. 232-234° C.

EXAMPLE 14

[0143]1-{2-(4′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0144] On working as described in Example 12 but by using4-tiifluoromethylbenzeneboronic acid instead of2-trifluoromethylbenzeneboronic acid in step 12b/, the title compound isobtained. M.p. 245-247° C.

1. Use of the compounds of formula (I)

in which R₁ is halogen, a CF₃, (C₁—C₄) alkyl or (C₁—C₄) alkoxy group; nis 0 or 1 R₂ is hydrogen or a (C₁—C₄) alkyl group; R₃ is hydrogen,(C₁—C₆) alkyl, (C₁—C₆) alkoxy; halogen, a CF₃ group, hydroxy, a groupselected from (C₃—C₇) cycloalkyl, phenyl, phenoxy, phenylmethyl orphenylethyl, said group being optionally mono- or polysubstituted on thephenyl group by halogen, CF₃, (C₁—C₄) alkyl or (C₁—C₄) alkoxy; R₄ and R₅is each independently hydrogen, (C₁—C₆) alkyl, (C₁—C₆) alkoxy, halogen,a CF₃ group or hydroxy; as well as their salts and solvates and theirquaternary ammonium salts, for the preparation of medicines designed forthe treatment and/or the prophylaxis of the diseases which involveneuronal degeneration.
 2. Use according to claim 1 of the compounds offormula (I) where n is zero.
 3. Use according to claim 1 or 2 of thecompounds of formula (I) where R₂ is hydrogen.
 4. Use according to oneof the claims 1 to 3 of the compounds of formula (I) where one of R₃, R₄and R₅ is hydrogen.
 5. Use according to one of the claims 1 to 4 of thecompounds of formula (I) where the group R₁ is a CF₃ group at position 3of the phenyl group.
 6. Use according to one of the claims 1 to 5 forthe preparation of medicines indicated in the treatment and/orprophylaxis of memory disorders, vascular dementia, post-encephaliticdisorders, post-apoplectic disorders, post-traumatic syndromes due to acranial traumatism, Alzeheimer's disease, senile dementia, subcorticaldementia, such as Huntington chorea and Parkinson's disease, dementiacaused by AIDS, neuropathies resulting from morbidity or damage tosympathetic or sensory nerves, cerebral diseases such as cerebral oedemaand spinocerebellar degenerations, degeneration of motoneurons like, forexample, amyotrophic lateral sclerosis.
 7. Use according to claim 6where the compound of formula (I) is coadministered or combined withother active ingredients acting on the CNS, selected from selective M₁cholinomimetics, NMDA antagonists and nootropic agents.
 8. Compound offormula (I′)

in which R′₁ is halogen, a CF₃, (C₁—C₄) alkyl or (C₁—C₄) alkoxy group;R′₂ is (C₁—C₆) alkyl, (C₁—C₆) alkoxy; halogen, a CF₃ group, hydroxy, agroup selected from (C₃—C₇) cycloalkyl, phenyl, phenoxy, phenylmethyl orphenylethyl, said group being optionally mono- or polysubstituted on thephenyl group by halogen, CF₃, (C₁—C₄) alkyl or (C₁—C₄) alkoxy; R′₃ ishydrogen, (C₁—C₆) alkyl, (C₁—C₆) alkoxy, halogen, a CF₃ group orhydroxy; as well as their salts and solvates and their quaternaryammonium salts.
 9. Compound according to claim 8 of formula (I″)

where X— is a pharmaceutically acceptable anion, Alk is (C₁—C₄) alkyland R′₁, R′₂ and R′₃ are as defined for the compounds (I′) in claim 8.10. Compound according to claim 8 selected from:1-{2-(3′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(2′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(4′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(4-isobutylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(4-benzylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(4-cyclohexylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(4′-fluorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(4-n-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(biphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(4-t-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(3,4-diethylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(3′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;1-{2-(4′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;as well as their salts and solvates.
 11. Process for the preparation ofthe compounds of formula (I′) according to claim 8, their salts orsolvates and their quaternary ammonium salts, characterized in that (a)an aryl-1,2,3,6-tetrahydropyride of formula (II)

 in which R′₁ is as defined for the compounds (I′) in claim 8, isreacted with a compound of formula (III)

in which R′₂ and R′₃ are as defined for the compounds (I′) in claim 8and L is a leaving group; and (b) the compound of formula (I′) thusobtained is isolated and optionally converted into one of its salts orsolvates or one of its quaternary ammonium salts.
 12. Pharmaceuticalcomposition containing as active ingredient a compound according to oneof the claims 8 to
 10. 13. Pharmaceutical composition containing asactive ingredient a compound of formula (I) such as defined in claim 1and a compound indicated in the symptomatic treatment of DAT, selectedfrom the acetylcholinesterase inhibitors, the M1 muscarinic agonists,the nicotinic agonists, the NMDA receptor antagonists and the nootropicagents, and their pharmaceutically acceptable salts.